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Beyond the smallest organisms, animals rely on tubes to transport cells, oxygen, nutrients, waste products, and a great variety of secretions. The cardiovascular system, lungs, gastrointestinal and genitourinary tracts, as well as major exocrine glands, are all composed of tubes. Paradoxically, despite their ubiquitous importance, most existing devices designed to study tubes are relatively complex to manufacture and/or utilize. The present work describes a simple method for generating tubes in vitro using nothing more than a low-cost 3D printer along with general lab supplies. The technology is termed "TruD", an acronym for true dimensional. Using this technology, it is readily feasible to cast tubes embedded in ECM with easy access to the lumen. The design is modular to permit more complex tube arrangements and to sustain flow. Importantly, by virtue of its simplicity, TruD technology enables typical molecular cell biology experiments where multiple conditions are assayed in replicate. [ABSTRACT FROM AUTHOR]

A multitude of aging-related factors and systemic conditions can cause lacrimal gland (LG) or salivary gland (SG) hypofunction leading to degenerative dry eye disease (DED) or dry mouth syndrome, respectively. Currently, there are no effective regenerative therapies that can fully reverse such gland hypofunction due to the lack of reproducible in vitro aging models or organoids required to develop novel treatments for multi-omic profiling. Previously, our research group successful developed three-dimensional (3D) bioassembly nanotechnologies towards the generation of functional exocrine gland organoids via magnetic 3D bioprinting platforms (M3DB). To meet the needs of our aging Asian societies, a next step was taken to design consistent M3DB protocols to engineer LG and SG organoid models with aging molecular and pathological features. Herein, a feasible step-by-step protocol was provided for producing both LG and SG organoids using M3DB platforms. Such protocol provided reproducible outcomes with final organoid products resembling LG or SG native parenchymal epithelial tissues. Both acinar and ductal epithelial compartments were prominent (21 ± 4.32% versus 42 ± 6.72%, respectively), and could be clearly identified in these organoids. Meanwhile, these can be further developed into aging signature models by inducing cellular senescence via chemical mutagenesis. The generation of senescence-like organoids will be our ultimate milestone aiming towards high throughput applications for drug screening and discovery, and for gene therapy investigations to reverse aging. [ABSTRACT FROM AUTHOR]

Background: Bipolar Transurethral Enucleation of the Prostate (B-TUEP) is recommended as a first-choice treatment for benign prostatic obstruction in prostates >80 ml. Differently, B-TUEP is only considered as an alternative option after TURP for smaller prostates (30–80 ml). The aim of our study is to assess the relation between prostate size and surgical outcomes after B-TUEP. Methods: We performed a retrospective analysis of data collected from 172 patients submitted to B-TUEP. Patients were segregated according to tertiles of prostate volume (PV) (≤60 ml, 61–110 ml, >110 ml). For each group we evaluated enucleation efficacy (enucleated weight/enucleation time), complication rates, urinary and sexual function parameters. Functional and sexual parameters were compared between groups at baseline, 1 and 3 months follow up. Descriptive statistics and linear and logistic regression models tested the association between PV and postoperative complications/outcomes. Results: Operative time and weight of enucleated adenomas increased along with prostate volumes (all p≤0.01). Enucleation efficacy was higher in men with PV >110 ml compared to other groups (p≤0.001). Length of hospital stay, catheterization time and rates of postoperative complications, such as transfusion and clot evacuation rates and bladder neck/urethral strictures, were comparable between groups. Urinary symptoms improved at 1-and 3-months in each group as compared to baseline evaluation (all p<0.01) but they did not differ according to PV. In each group maximum urinary flow and post-void residual volume significantly improved at 3 months compared to baseline (all p≤0.01), without differences according to PV. Sexual symptoms were similar between groups at each follow up assessment. At multivariable linear and logistic regression analysis, prostate volume was not associated with postoperative functional outcomes and complications. Conversely, patient's comorbid status and antiplatelet/anticoagulation use were independently associated with postoperative complications. Conclusion: According to our findings, B-TUEP should be considered a "size independent procedure" as it can provide symptom relief in men with prostates of all sizes with the same efficacy and safety profile. [ABSTRACT FROM AUTHOR]

Background: Magnetic resonance imaging (MRI) is essential in the detection and staging of prostate cancer. However, improved tools to distinguish between low-risk and high-risk cancer are needed in order to select the appropriate treatment. Purpose: To investigate the diagnostic potential of signal fractions estimated from a two-component model using combined T2- and diffusion-weighted imaging (T2-DWI). Material and methods: 62 patients with prostate cancer and 14 patients with benign prostatic hyperplasia (BPH) underwent combined T2-DWI (TE = 55 and 73 ms, b-values = 50 and 700 s/mm2) following clinical suspicion of cancer, providing a set of 4 measurements per voxel. Cancer was confirmed in post-MRI biopsy, and regions of interest (ROIs) were delineated based on radiology reporting. Signal fractions of the slow component (SFslow) of the proposed two-component model were calculated from a model fit with 2 free parameters, and compared to conventional bi- and mono-exponential apparent diffusion coefficient (ADC) models. Results: All three models showed a significant difference (p<0.0001) between peripheral zone (PZ) tumor and normal tissue ROIs, but not between non-PZ tumor and BPH ROIs. The area under the receiver operating characteristics curve distinguishing tumor from prostate voxels was 0.956, 0.949 and 0.949 for the two-component, bi-exponential and mono-exponential models, respectively. The corresponding Spearman correlation coefficients between tumor values and Gleason Grade Group were fair (0.370, 0.499 and -0.490), but not significant. Conclusion: Signal fraction estimates from a two-component model based on combined T2-DWI can differentiate between tumor and normal prostate tissue and show potential for prostate cancer diagnosis. The model performed similarly to conventional diffusion models. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the most common cancer and the third most frequent cause of male cancer death in Germany. MicroRNAs (miRNA) appear to be involved in the development and progression of PCa. A diagnostic differentiation from benign prostate hyperplasia (BPH) is often only possible through transrectal punch biopsy. This procedure is described as painful and carries risks. It was investigated whether urinary miRNAs can be used as biomarkers to differentiate the prostate diseases above. Therefore urine samples from urological patients with BPH (25) or PCa (28) were analysed using Next-Generation Sequencing to detect the expression profile of total and exosomal miRNA/piRNA. 79 miRNAs and 5 piwi-interacting RNAs (piRNAs) were significantly differentially expressed (adjusted p-value < 0.05 and log2-Fc > 1 or < -1). Of these, 6 miRNAs and 2 piRNAs could be statistically validated (AUC on test cohort > = 0.7). In addition, machine-learning algorithms were used to identify a panel of 22 additional miRNAs, whose interaction makes it possible to differentiate the groups as well. There are promising individual candidates for potential use as biomarkers in prostate cancer. The innovative approach of applying machine learning methods to this kind of data could lead to further small RNAs coming into scientific focus, which have so far been neglected. [ABSTRACT FROM AUTHOR]

Facilitating clinical translation of quantitative imaging techniques has been suggested as means of improving interobserver agreement and diagnostic accuracy of multiparametric magnetic resonance imaging (mpMRI) of the prostate. One such technique, magnetic resonance fingerprinting (MRF), has significant competitive advantages over conventional mapping techniques in terms of its multi-site reproducibility, short scanning time and inherent robustness to motion. It has also been shown to improve the detection of clinically significant prostate cancer when added to standard mpMRI sequences, however, the existing studies have all been conducted on 3.0 T MRI systems, limiting the technique's use on 1.5 T MRI scanners that are still more widely used for prostate imaging across the globe. The aim of this proof-of-concept study was, therefore, to evaluate the cross-system reproducibility of prostate MRF T1 in healthy volunteers (HVs) using 1.5 and 3.0 T MRI systems. The initial validation of MRF T1 against gold standard inversion recovery fast spin echo (IR-FSE) T1 in the ISMRM/NIST MRI system revealed a strong linear correlation between phantom-derived MRF and IR-FSE T1 values was observed at both field strengths (R2 = 0.998 at 1.5T and R2 = 0.993 at 3T; p = < 0.0001 for both). In young HVs, inter-scanner CVs demonstrated marginal differences across all tissues with the highest difference of 3% observed in fat (2% at 1.5T vs 5% at 3T). At both field strengths, MRF T1 could confidently differentiate prostate peripheral zone from transition zone, which highlights the high quantitative potential of the technique given the known difficulty of tissue differentiation in this age group. The high cross-system reproducibility of MRF T1 relaxometry of the healthy prostate observed in this preliminary study, therefore, supports the technique's prospective clinical validation as part of larger trials employing 1.5 T MRI systems, which are still widely used clinically for routine mpMRI of the prostate. [ABSTRACT FROM AUTHOR]

Neuroendocrine prostate cancer (NEPrCa) arises de novo or after accumulation of genomic alterations in pre-existing adenocarcinoma tumors in response to androgen deprivation therapies. We have provided evidence that small extracellular vesicles released by PrCa cells and containing the αVβ3 integrin promote neuroendocrine differentiation of PrCa in vivo and in vitro. Here, we examined αVβ3 integrin expression in three murine models carrying a deletion of PTEN (SKO), PTEN and RB1 (DKO), or PTEN, RB1 and TRP53 (TKO) genes in the prostatic epithelium; of these three models, the DKO and TKO tumors develop NEPrCa with a gene signature comparable to those of human NEPrCa. Immunostaining analysis of SKO, DKO and TKO tumors shows that αVβ3 integrin expression is increased in DKO and TKO primary tumors and metastatic lesions, but absent in SKO primary tumors. On the other hand, SKO tumors show higher levels of a different αV integrin, αVβ6, as compared to DKO and TKO tumors. These results are confirmed by RNA-sequencing analysis. Moreover, TRAMP mice, which carry NEPrCa and adenocarcinoma of the prostate, also have increased levels of αVβ3 in their NEPrCa primary tumors. In contrast, the αVβ6 integrin is only detectable in the adenocarcinoma areas. Finally, analysis of 42 LuCaP patient-derived xenografts and primary adenocarcinoma samples shows a positive correlation between αVβ3, but not αVβ6, and the neuronal marker synaptophysin; it also demonstrates that αVβ3 is absent in prostatic adenocarcinomas. In summary, we demonstrate that αVβ3 integrin is upregulated in NEPrCa primary and metastatic lesions; in contrast, the αVβ6 integrin is confined to adenocarcinoma of the prostate. Our findings suggest that the αVβ3 integrin, but not αVβ6, may promote a shift in lineage plasticity towards a NE phenotype and might serve as an informative biomarker for the early detection of NE differentiation in prostate cancer. [ABSTRACT FROM AUTHOR]

Our previous studies have shown that Zika virus (ZIKV) replicates in human prostate cells, suggesting that the prostate may serve as a long-term reservoir for virus transmission. Here, we demonstrated that the innate immune responses generated to three distinct ZIKV strains (all isolated from human serum) were significantly different and dependent on their passage history (in mosquito, monkey, or human cells). In addition, some of these phenotypic differences were reduced by a single additional cell culture passage, suggesting that viruses that have been passaged more than 3 times from the patient sample will no longer reflect natural phenotypes. Two of the ZIKV strains analyzed induced high levels of the IP-10 chemokine and IFNγ in human prostate epithelial and stromal mesenchymal stem cells. To further understand the importance of these innate responses on ZIKV replication, we measured the effects of IP-10 and its downstream receptor, CXCR3, on RNA and virus production in prostate cells. Treatment with IP-10, CXCR3 agonist, or CXCR3 antagonist significantly altered ZIKV viral gene expression, depending on their passage in cells of relevant hosts (mosquito or human). We detected differences in gene expression of two primary CXCR3 isoforms (CXCR3-A and CXCR3-B) on the two cell types, possibly explaining differences in viral output. Lastly, we examined the effects of IP-10, agonist, or antagonist on cell death and proliferation under physiologically relevant infection rates, and detected no significant differences. Although we did not measure protein expression directly, our results indicate that CXCR3 signaling may be a target for therapeutics, to ultimately stop sexual transmission of this virus. [ABSTRACT FROM AUTHOR]

The tumour micro-environment (TME) plays a crucial role in the onset and progression of prostate cancer (PCa). Here we studied the potential of a selected panel of TME-markers to predict clinical recurrence (CLR) in PCa. Patient cohorts were matched for the presence or absence of CLR 5 years post-prostatectomy. Tissue micro-arrays (TMA) were composed with both prostate non-tumour (PNT) and PCa tissue and subsequently processed for immunohistochemistry (IHC). The IHC panel included markers for cancer activated fibroblasts (CAFs), blood vessels and steroid hormone receptors ((SHR): androgen receptor (AR), progesterone receptor (PR) and estrogen receptor (ER)). Stained slides were digitalised, selectively annotated and analysed for percentage of marker expression with standardized and validated image analysis algorithms. A univariable analysis identified several TME markers with significant impact on CR: expression of CD31 (vascular marker) in PNT stroma, expression of alpha smooth muscle actin (αSMA) in PCa stroma, and PR expression ratio between PCa stroma and PNT stroma. A multivariable model, which included CD31 expression (vascular marker) in PNT stroma and PR expression ratio between PCa stroma and PNT stroma, could significantly stratify patients for CLR, with the identification of a low risk and high-risk subgroup. If validated and confirmed in an independent prospective series, this subgroup might have clinical potential for PCa patient stratification. [ABSTRACT FROM AUTHOR]

In addition to breast, ovarian, and pancreatic cancers, BRCA1/2 genes have been associated with prostate cancer (PC). However, the role of BRCA1/2-associated family cancer history (FCH) has remained unexplored in treating these four cancer types as a homogenous pathophysiological group. We aimed to clarify the relationship between BRCA1/2-associated FCH and PC, and to assess its relationship with cancer aggressiveness. Patient characteristics, positive family history of BRCA1/2-associated cancer, and cancer characteristics (Gleason score, prostate specific antigen level at diagnosis, and clinical tumor stage) were analyzed. Among the 1,985 eligible candidates, 473 (23.83%) patients had adequately detailed FCH, obtained via questionnaire, and were thus included in the study. BRCA1/2-associated FCH was observed in 135 (28.54%) patients with PC (68, 14.38%), breast (44, 9.30%), pancreatic (31, 6.55%), or ovarian (8, 1.69%) cancers. BRCA1/2-associated FCH was not significantly associated with high Gleason score (≥ 8). Patients with BRCA-associated FCH were less likely to present with high clinical tumor stage, and no difference was observed in prostate-specific antigen level, presence of metastatic lesions at diagnosis, or likelihood of high-risk classification between patients with and without BRCA-associated FCH. This is the first report of BRCA1/2-associated FCH in Japanese men, indicating that family history did not affect the severity or aggressiveness of PC. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer is the second most common cancer among men in Uganda, with over 2086 incident cases in 2018. This study's objective was to report the clinical characteristics and primary management of men diagnosed with prostate cancer at the Uganda Cancer Institute from 1st January 2015 to 31st December 2019. Methods: Records from all men diagnosed with Prostate cancer at the Uganda Cancer Institute from 1st January 2015 to 31st December 2019 were reviewed. Clinical characteristics and primary treatment were recorded. Risk categorization was done using the European Society for Medical Oncology prostate cancer risk group classification. Results: A total of 874 medical records for men diagnosed with prostate cancer was retrieved. The median age was 70 years (interquartile range 64–77). In this study, 501 (57.32%) patients had localized disease. Among patients with localized disease, 2 (0.23%) were classified as low-risk, 5 (0.53%) as intermediate-risk, and 494 (56.52%) as high-risk. Three hundred seventy-three (373) patients had metastatic disease at diagnosis. Among patients with distant metastases, the most common site of metastases was bone 143 (16.36%), followed by spinal cord 54 (6.18%), abdomen 22 (2.52%), and lungs 14 (1.60%). Regarding the primary treatment options majority of the patients were on chemotherapy 384(43.94%) followed by hormonal therapy 336 (38.44%) and radiotherapy 127 (14.53%). Conclusion: The majority of the patients diagnosed with prostate cancer at the Uganda Cancer Institute presented with advanced disease. The primary treatments were mostly chemotherapy, hormonal therapy, and radiotherapy. There is a need to improve prostate cancer screening in regional health care facilities and the communities to enhance early detection and management of prostate cancer. [ABSTRACT FROM AUTHOR]

Bone is one of the most common sites of metastasis from advanced solid tumors. Bone metastasis is a leading cause of pain and increases the risk of skeletal-related events (SREs) in cancer patients. In addition to affecting the quality of life, it also increases the medical costs and mortality risk. We aimed to examine the occurrence of bone metastasis and SREs in Korean cancer patients using a nationwide health database. Using claims data from the National Health Insurance Service-National Sample Cohort (2002–2013), we extracted the data of bone metastasis patients diagnosed with any of the seven major cancers in Korea from January 2002 to December 2010. Selected SREs included pathologic fracture, spinal cord compression, radiation therapy, and palliative bone surgery. We used time-to-event analysis to estimate patient survival after bone metastasis. A total of 21,562 newly diagnosed cancer patients were identified; bone metastases developed in 1,849 patients (breast cancer, 18.8%; prostate cancer, 17.5%; lung cancer, 13.7%). The median time from primary cancer diagnosis to bone metastasis was 18.9 months. The cumulative incidence of SREs was 45.1% in all bone metastasis patients. The most common cancer type was lung cancer (53.4%), followed by liver (50.9%), prostate (45.9%), breast (43.6%), and colorectal (40.2%) cancers. Almost all SREs developed 1 month after bone metastasis, except in patients with breast and prostate cancers (median: 5.9 months in breast cancer and 4.7 months in prostate cancer). Survival duration after the development of bone metastasis was < 6 months in stomach, liver, colorectal, and lung cancer patients. Breast and prostate cancer patients survived for > 1 year after the occurrence of SREs. This study reveals the epidemiology of bone metastasis and SREs in Korean cancer patients, and the findings can be used to assess the actual bone health status of cancer patients. [ABSTRACT FROM AUTHOR]

Studies of the normal functions and diseases of the prostate request in vivo models that maintain the tissue architecture and the multiple-cell type compartments of human origin in order to recapitulate reliably the interactions of different cell types. Cell type-specific transcriptomes are critical to reveal the roles of each cell type in the functions and diseases of the prostate. A primary prostate tissue xenograft model was developed using fresh human prostate tissue specimens transplanted onto male mice that were castrated surgically and implanted with a device to maintain circulating testosterone levels comparable to adult human males. Endothelial cells and epithelial cells were isolated from 7 fresh human prostate tissue specimens and from primary tissue xenografts established from 9 fresh human prostate tissue specimens, using antibody-conjugated magnetic beads specific to human CD31 and human EpCAM, respectively. Transcriptomes of endothelial, epithelial and stromal cell fractions were obtained using RNA-Seq. Global and function-specific gene expression profiles were compared in inter-cell type and inter-tissue type manners. Gene expression profiles in the individual cell types isolated from xenografts were similar to those of cells isolated from fresh tissue, demonstrating the value of the primary tissue xenograft model for studies of the inter-relationships between prostatic cell types and the role of such inter-relationships in organ development, disease progression, and response to drug treatments. [ABSTRACT FROM AUTHOR]

To explore the shape characteristics of ablation lesions created via laser ablation (LA), radiofrequency ablation (RFA) and microwave ablation (MWA) in canine prostates and the clinical significance of these characteristics, six adult male beagles were randomly assigned to the LA, RFA, and MWA groups. These ablations were performed with common parameters applied in clinical practice (LA, 3 W/1200 J; RFA and MWA, 30 W/120 s). One ablation lesion was created in each lobe of the prostate via the ablation technique, resulting in a total of twelve ablation lesions. Transrectal ultrasound (TRUS) was used as guidance during puncture and to monitor changes in the ablation lesions. Finally, the ablation efficacy was assessed using transrectal contrast-enhanced ultrasonography (CEUS), and the transverse diameter (TRD), anteroposterior diameter (APD) and longitudinal diameter (LD) of each ablation lesion were measured. The volume (V) and the ratio (R) value were calculated. R reflects the shape characteristic of the ablation lesion (the R value close to 1.0 indicates a more spherical shape). The R values of the ablation lesions were 0.89 ± 0.02, 0.72 ± 0.01, and 0.65 ± 0.03 for RFA, MWA and LA, respectively, and they were significantly different (P = 0.027). The volumes of the ablation lesions were 2.17 ± 0.10 ml, 1.51 ± 0.20 ml, and 0.79 ± 0.07 ml for MWA, LA and RFA, respectively, and they were also significantly different (P = 0.001). The three abovementioned thermal ablation techniques with common parameters in clinical practice can be used for ablation in the prostate. The shapes and volumes of the ablation lesions of the three techniques were varied: The RFA-created lesions had the lowest volumes and were more spherical in shape, demonstrating that RFA could be used for the treatment of relatively small lesions or tumours adjacent to vital organs. The MWA lesions had the largest size with a spherical shape, which could be advantageous for the ablation of tumours with relatively large sizes. The sizes of the ablation lesions created via LA were between those of RFA and MWA but presented more oval in shape, suggesting that this method is highly appropriate for the ablation of benign prostatic hyperplasia (BPH). [ABSTRACT FROM AUTHOR]

Canine prostate adenocarcinoma (PAC) and transitional cell carcinoma (TCC) of prostate and urinary bladder are highly invasive and metastatic tumors of closely neighbored organs. Cell lines are valuable tools to investigate tumor mechanisms and therapeutic approaches in vitro. PAC in dogs is infrequent, difficult to differentiate from TCC and usually characterized by poor prognosis, enhancing the value of the few available cell lines. However, as cell lines adapt to culturing conditions, a thorough characterization, ideally compared to original tissue, is indispensable. Herein, six canine PAC cell lines and three TCC cell lines were profiled by immunophenotype in comparison to respective original tumor tissues. Three of the six PAC cell lines were derived from primary tumor and metastases of the same patient. Further, two of the three TCC cell lines were derived from TCCs invading into or originating from the prostate. Cell biologic parameters as doubling times and chemoresistances to commonly used drugs in cancer treatment (doxorubicin, carboplatin and meloxicam) were assessed. All cell lines were immunohistochemically close to the respective original tissue. Compared to primary tumor cell lines, metastasis-derived cell lines were more chemoresistant to doxorubicin, but equally susceptive to carboplatin treatment. Two cell lines were multiresistant. COX-2 enzyme activity was demonstrated in all cell lines. However, meloxicam inhibited prostaglandin E2 production in only seven of nine cell lines and did neither influence metabolic activity, nor proliferation. The characterized nine cell lines represent excellent tools to investigate PAC as well as TCC in prostate and urinary bladder of the dog. Furthermore, the profiled paired cell lines from PAC primary tumor and metastasis provide the unique opportunity to investigate metastasis-associated changes PAC cells undergo in tumor progression. The combination of nine differently chemoresistant PAC and TCC cell lines resembles the heterogeneity of canine lower urinary tract cancer. [ABSTRACT FROM AUTHOR]

Objectives: To examine and compare changes in strength and physical function from pre- to post-diagnosis among men with prostate cancer (PC, [cases]) and matched non-cancer controls identified from the Health, Aging and Body Composition (Health ABC) study. Materials and methods: We conducted a longitudinal analysis of 2 strength and 3 physical function-based measures among both cases and controls, identified from a large cohort of community living older adults enrolled in the Health ABC study. We plotted trajectories for each measure and compared cases vs. controls from the point of diagnosis onwards using mixed-effects regression models. For cases only, we examined predictors of poor strength or physical function. Results: We identified 117 PC cases and 453 matched non-cancer controls (50% African Americans). At baseline, there were no differences between cases and controls in demographic factors, comorbidities or self-reported physical function; however, cases had slightly better grip strength (44.6 kg vs. 41.0 kg, p<0.01), quadriceps strength (360.5 Nm vs. 338.7 Nm, p = 0.02) and Health ABC physical performance battery scores (2.4 vs. 2.3, p = 0.01). All men experienced similar declines in strength and physical function over an equivalent amount of time. The loss of quad strength was most notable, with losses of nearly two-thirds of baseline strength over approximately 7 years of follow up. Conclusions: Among both cases and controls, strength and physical function decline with increasing age. The largest declines were seen in lower body strength. Regular assessments should guide lifestyle interventions that can offset age- and treatment-related declines among men with PC. [ABSTRACT FROM AUTHOR]

Mounting evidence indicates that coffee, a commonly consumed beverage worldwide, is inversely associated with various chronic diseases and overall mortality. Few studies have evaluated the effect of coffee drinking on telomere length, a biomarker of chromosomal integrity, and results have been inconsistent. Understanding this association may provide mechanistic insight into associations of coffee with health. The aim of our study was to test the hypothesis that heavier coffee intake is associated with greater likelihood of having above-median telomere length. We evaluated the cross-sectional association between coffee intake and relative telomere length using data from 1,638 controls from four previously conducted case-control studies nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Coffee intake was assessed using a food frequency questionnaire, and relative telomere length was measured from buffy-coat, blood, or buccal cells. We used unconditional logistic regression models to generate multivariable-adjusted, study-specific odds ratios for the association between coffee intake and relative telomere length. We then conducted a random-effects meta-analysis to determine summary odds ratios. We found that neither summary continuous (OR = 1.01, 95% CI = 0.99–1.03) nor categorical (OR <3 cups/day vs. none = 1.37, 95% CI = 0.71–2.65; OR ≥3 cups/day vs. none = 1.47, 95% CI = 0.81–2.66) odds ratio estimates of coffee drinking and relative telomere length were statistically significant. However, in the largest of the four contributing studies, moderate (<3 cups/day) and heavy coffee drinkers (≥3 cups/day) were 2.10 times (95% CI = 1.25, 3.54) and 1.93 times as likely (95% CI = 1.17, 3.18) as nondrinkers to have above-median telomere length, respectively. In conclusion, we found no evidence that coffee drinking is associated with telomere length. Thus, it is unlikely that telomere length plays a role in potential coffee-disease associations. [ABSTRACT FROM AUTHOR]

Concentrations of free amino acids and [K+] in human sweat can be many times higher than in plasma. Conversely, [Na+] and [Cl-] in sweat are hypotonic to plasma. It was hypothesised that the amino acids and K+ were directly or indirectly associated with the resorption of Na+ and Cl- in the sweat duct. The implication would be that, as resources of these components became limiting during prolonged exercise then the capacity to resorb [Na+] and [Cl-] would diminish, resulting in progressively higher levels in sweat. If this were the case, then [Na+] and [Cl-] in sweat would have inverse relationships with [K+] and the amino acids during exercise. Forearm sweat was collected from 11 recreational athletes at regular intervals during a prolonged period of cycling exercise after 15, 25, 35, 45, 55 and 65 minutes. The subjects also provided passive sweat samples via 15 minutes of thermal stimulation. The sweat samples were analysed for concentrations of amino acids, Na+, Cl-, K+, Mg2+ and Ca2+. The exercise sweat had a total amino acid concentration of 6.4 ± 1.2mM after 15 minutes which was lower than the passive sweat concentration at 11.6 ± 0.8mM (p<0.05) and showed an altered array of electrolytes, indicating that exercise stimulated a change in sweat composition. During the exercise period, [Na+] in sweat increased from 23.3 ± 3.0mM to 34.6 ± 2.4mM (p<0.01) over 65 minutes whilst the total concentrations of amino acids in sweat decreased from 6.4 ± 1.2mM to 3.6 ± 0.5mM. [Na+] showed significant negative correlations with the concentrations of total amino acids (r = -0.97, p<0.05), K+ (r = -0.93, p<0.05) and Ca2+ (r = -0.83, p<0.05) in sweat. The results supported the hypothesis that amino acids and K+, as well as Ca2+, were associated with resorption of Na+ and Cl-. [ABSTRACT FROM AUTHOR]

Background: Cancers of the head and neck have a high mortality rate, and roughly 10% of the patients die within six months of diagnosis. To our knowledge little has been written about this group. We wished to identify risk factors for early death, to predict and monitor patients at risk better and, if possible, avoid unjustified major treatment. Methods and findings: This population-based nationwide study from the Swedish Head and Neck Cancer Register (SweHNCR) included data from 2008–2015 and 9733 patients at potential risk of early death. A total of 925 (9.5%) patients died within six months. For every year older the patients became, the risk of early death increased by 2.3% (p<0.001). The relative risk of death was 3.37 times higher (237%) for patients with WHO score 1 compared with WHO score 0. A primary tumour in the hypopharynx correlated with a 24% increased risk over the oral cavity (p<0.024). Patients with stage IV disease had a 3.7 times greater risk of early death than those with stage I (p<0.001). As expected, a 12 times increased risk of early death was noted in the palliative treatment group, compared to the curative group. Limitations to this study were that the actual cause of death was not recorded in the SweHNCR, and that socioeconomic factors, alcohol consumption, smoking habits, and HPV status, were not reported in SweHNCR until 2015. However, the fact that this is a population-based nationwide study including 9733 patients compensates for some of these limitations. Conclusions: Identification of patients at increased risk of early death shows that older patients with advanced disease, increased WHO score, primary tumour in the hypopharynx, and those given palliative treatment, are more likely than the others to die from head and neck cancer within six months of diagnosis. [ABSTRACT FROM AUTHOR]

The growth inhibitory efficacy of methylseleninic acid (MSA) in prostate cancer cells has been documented extensively. However, our understanding of the immediate targets that are key to the growth inhibitory effects of MSA remains limited. Here, using multiple preclinical prostate cancer models, we demonstrated in vitro and in vivo that GDF15 is a most highly induced, immediate target of MSA. We further showed that knockdown of GDF15 mitigates MSA inhibition of cell proliferation and induction of apoptosis. Analysis of gene expression data from over 1000 primary and 200 metastatic prostate cancer samples revealed that GDF15 expression is decreased in metastatic prostate cancers compared to primary tumors and that lower GDF15 levels in primary tumors are associated with higher Gleason scores and shorter survival of the patients. Additionally, pathways that are negatively correlated with GDF15 levels in clinical samples are also negatively correlated with MSA treatment in cultured cells. Since most, if not all, of these pathways have been implicated in prostate cancer progression, suppressing their activities by inducing GDF15 is consistent with the anticancer effects of MSA in prostate cancer. Overall, this study provides support for GDF15 as an immediate target of MSA in prostate cancer cells. [ABSTRACT FROM AUTHOR]

The bovine dry period is a non-lactating period between consecutive lactations characterized by mammary gland involution and redevelopment phases to replace senescent mammary epithelial cells with active cells primed for the next lactation. Dairy cows exposed to heat stress during the dry period experience milk yield reductions between 3–7.5 kg/d in the next lactation, partially attributed to processes associated with mammary cell growth and turnover during the dry period. However, the carry-over impact of dry period heat stress on mammary morphology during lactation has yet to be determined. In the current study, we hypothesized that exposure to heat stress during the dry period would alter alveolar microstructure and cellular turnover (i.e. proliferation and apoptosis) during lactation. Cows were either subjected to heat stress (HT, access to shade; n = 12) or cooling (CL, access to shade, fans, and soakers; n = 12) for a 46 d dry period. Upon calving, all cows were treated similarly with access to cooling for their entire lactation. Six cows per treatment were randomly selected for mammary gland biopsies at 14, 42, and 84 days in milk. Tissues were sectioned and stained for histological analysis. During lactation, HT cows produced 4 kg less colostrum and 3.7 kg less milk compared with CL cows. Lactating mammary gland microstructure was impacted after exposure to dry period heat stress; HT cows had fewer alveoli and a higher proportion of connective tissue in the mammary gland relative to CL cows, however alveolar area was similar between treatments. Rates of mammary epithelial cell proliferation and apoptosis were similar between treatment groups. This suggests that heat stress exposure during the dry period leads to reductions in milk yield that could be caused, in part, by a reduction in alveoli number in the lactating mammary gland but not to dynamic alterations in cellular turnover once lactation is established. [ABSTRACT FROM AUTHOR]

Congenital hyperinsulinism (CHI) is characterised by inappropriate insulin secretion causing profound hypoglycaemia and brain damage if inadequately controlled. Pancreatic tissue isolated from patients with diffuse CHI shows abnormal proliferation rates, the mechanisms of which are not fully resolved. Understanding cell proliferation in CHI may lead to new therapeutic options, alongside opportunities to manipulate β-cell mass in patients with diabetes. We aimed to generate cell-lines from CHI pancreatic tissue to provide in vitro model systems for research. Three pancreatic mesenchymal stem cell-lines (CHIpMSC1-3) were derived from patients with CHI disease variants: focal, atypical and diffuse. All CHIpMSC lines demonstrated increased proliferation compared with control adult-derived pMSCs. Cell cycle alterations including increased CDK1 levels and decreased p27Kip1 nuclear localisation were observed in CHIpMSCs when compared to control pMSCs. In conclusion, CHIpMSCs are a useful in vitro model to further understand the cell cycle alterations leading to increased islet cell proliferation in CHI. [ABSTRACT FROM AUTHOR]

Background: Hyperhidrosis is a pathological condition defined by excessive sweating beyond thermoregulatory physiological needs, which can cause substantial psychological impact and impairment of daily activities. Studies regarding its prevalence, however, are scarce and vary widely in their findings. The population of medical students is a particularly interesting subset for its recurring demand of physical contact during patient examination or procedures, and the potential for professional adversity. We aimed at furthering the comprehension of this disease prevalence and characteristics among medical students. Methods: Questionnaires inquiring about the presence and characteristics of Primary Hyperhidrosis (PH) were applied through either written or digital means to all eligible medical students enrolled in three Medical Schools in the State of Rio de Janeiro who agreed to take part in the study. Demographic data regarding gender, ethnicity, current age, weight and height was collected in addition to clinical data (sweat site, age of onset, familial history, severity and previous treatments). Severity was evaluated through the Hyperhidrosis Disease Severity Scale (HDSS) and a symptoms survey. Findings: Our response rate was roughly 1/3 of all eligible students (900/2700). PH prevalence was 20.56% (185/900). It was similar between men and women (23.08% and 19.41%, respectively) and strongly associated with family history of the disease (Prevalence Ratio of 4.27). Regarding ethnicity, of the total sample 73.78% (664/900) self-declared white, among which 19.28% (128/664) had PH. Mixed-race and other ethnicities encompassed 26.22% (236/900) of the sample, among which 24.15% (57/236) had PH. Most positive subjects (64.32%) presented associated forms of PH. Overall involvement of each site (both associated and isolated) was: 63.78% axillary, 50.81% palmar, 43.24% plantar, 20.54% craniofacial, 18.38% facial flushing and 2.16% gustatory sweating. Mean current age was 23.11(±4.04) years for PH patients, and age of onset was ≤18 years in 93.94% of cases. Regarding body mass index (BMI), 71.09% of PH patients had BMI<25kg/m2 and only 4.69% presented BMI≥30kg/m2, none ≥35kg/m2. Some degree of life quality impairment was reported by 89.20% of PH patients, and 23.89% had HDSS 3 or 4 (moderate to severe). Conclusions: PH prevalence among Rio de Janeiro medical students was 20.56%, similar between men and women, predominating associated presentations, axillary, palmar and plantar sites, strong familial history, age of onset before 18 years, and some degree of life impairment. [ABSTRACT FROM AUTHOR]

Hyperinsulinemia affects 72% of Fanconi anemia (FA) patients and an additional 25% experience lowered glucose tolerance or frank diabetes. The underlying molecular mechanisms contributing to the dysfunction of FA pancreas β cells is unknown. Therefore, we sought to evaluate the functional role of FANCA, the most commonly mutated gene in FA, in glucose-stimulated insulin secretion (GSIS). This study reveals that FANCA or FANCB knockdown impairs GSIS in human pancreas β cell line EndoC-βH3. To identify potential pathways by which FANCA might regulate GSIS, we employed a proteomics approach to identify FANCA protein interactions in EndoC-βH3 differentially regulated in response to elevated glucose levels. Glucose-dependent changes in the FANCA interaction network were observed, including increased association with other FA family proteins, suggesting an activation of the DNA damage response in response to elevated glucose levels. Reactive oxygen species increase in response to glucose stimulation and are necessary for GSIS in EndoC-βH3 cells. Glucose-induced activation of the DNA damage response was also observed as an increase in the DNA damage foci marker γ-H2AX and dependent upon the presence of reactive oxygen species. These results illuminate the role of FANCA in GSIS and its protein interactions regulated by glucose stimulation that may explain the prevalence of β cell-specific endocrinopathies in FA patients. [ABSTRACT FROM AUTHOR]

Pilocarpine is an M3 muscarinic agonist that is widely used for the treatment of xerostomia caused by various diseases and medical conditions. Pilocarpine induced the secretion of salivary fluid in perfused submandibular glands of rats. The secretion of salivary fluid observed after removal of pilocarpine was referred to as residual fluid secretion. The volume of fluid and time of the residual secretion depended on the dose of pilocarpine. Such a residual effect of pilocarpine was observed on fluid secretion via the paracellular pathway and oxygen consumption. When a muscarinic antagonist was added to the perfusate immediately after cessation of pilocarpine, residual secretion of salivary fluid did not occur. These observations indicate that the residual secretion of salivary fluid is a characteristics of the interaction of pilocarpine with muscarinic receptors. [ABSTRACT FROM AUTHOR]

Background: Risk models (RM) need external validation to assess their value beyond the setting in which they were developed. We validated a RM combining mpMRI and clinical parameters for the probability of harboring significant prostate cancer (sPC, Gleason Score ≥ 3+4) for biopsy-naïve men. Material and methods: The original RM was based on data of 670 biopsy-naïve men from Heidelberg University Hospital who underwent mpMRI with PI-RADS scoring prior to MRI/TRUS-fusion biopsy 2012–2015. Validity was tested by a consecutive cohort of biopsy-naïve men from Heidelberg (n = 160) and externally by a cohort of 133 men from University College London Hospital (UCLH). Assessment of validity was performed at fusion-biopsy by calibration plots, receiver operating characteristics curve and decision curve analyses. The RM`s performance was compared to ERSPC-RC3, ERSPC-RC3+PI-RADSv1.0 and PI-RADSv1.0 alone. Results: SPC was detected in 76 men (48%) at Heidelberg and 38 men (29%) at UCLH. The areas under the curve (AUC) were 0.86 for the RM in both cohorts. For ERSPC-RC3+PI-RADSv1.0 the AUC was 0.84 in Heidelberg and 0.82 at UCLH, for ERSPC-RC3 0.76 at Heidelberg and 0.77 at UCLH and for PI-RADSv1.0 0.79 in Heidelberg and 0.82 at UCLH. Calibration curves suggest that prevalence of sPC needs to be adjusted to local circumstances, as the RM overestimated the risk of harboring sPC in the UCLH cohort. After prevalence-adjustment with respect to the prevalence underlying ERSPC-RC3 to ensure a generalizable comparison, not only between the Heidelberg and die UCLH subgroup, the RM`s Net benefit was superior over the ERSPC`s and the mpMRI`s for threshold probabilities above 0.1 in both cohorts. Conclusions: The RM discriminated well between men with and without sPC at initial MRI-targeted biopsy but overestimated the sPC-risk at UCLH. Taking prevalence into account, the model demonstrated benefit compared with clinical risk calculators and PI-RADSv1.0 in making the decision to biopsy men at suspicion of PC. However, prevalence differences must be taken into account when using or validating the presented risk model. [ABSTRACT FROM AUTHOR]

Background and aims: The revised Atlanta classification is widely used for the evaluation of acute pancreatitis (AP) severity. However, this classification cannot be used within 48 hours of AP onset. The aim of this study was to investigate the predictive factors of mortality in patients with AP on admission. Methods: We evaluated the association between AP mortality and clinical parameters at the time of admission in patients with AP from April 2013 to December 2017 at one university hospital and one tertiary care referral center. Results: A total of 203 consecutive patients were enrolled. Nine patients (4.4%) died despite multidisciplinary treatment. In a multivariable analysis, hematocrit ≥ 40% (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.01–1.13; P = 0.021), blood urea nitrogen (BUN) ≥ 40 mg/dL (OR, 1.26; 95% CI, 1.11–1.42; P < 0.001), base excess < -3.0 mmol/L (OR, 1.15; 95% CI, 1.04–1.26; P = 0.004), and inflammation extending to the rectovesical excavation (OR, 1.19; 95% CI, 1.10–1.30; P < 0.001) on admission were significantly associated with mortality. Conclusion: Among the imaging findings, inflammation extending to the rectovesical excavation was the only independent predictive factor for mortality in AP. This simple finding, obtained on computed tomography without contrast agent on admission, might be a promising prognostic factor for AP. [ABSTRACT FROM AUTHOR]

Purpose: mARC (modulated arc) is the arc therapy technique provided by Siemens. The present study analyses the dose distributions and treatment times corresponding to preoperative rectal cancer mARC treatments. The results are compared to those corresponding to 3D-CRT plans. Methods: The plans of 30 patients, each having one mARC and one 3D-CRT plan, were evaluated. Every plan was calculated on a sequential two-phase treatment scheme with prescription doses of 45 Gy in the initial phase and 5.4 Gy in the boost phase. Dosimetric parameters and mean DVHs corresponding to the PTVs and OARs were assessed for both techniques. Results: All mARC plans were considered valid for treatment and yielded a highly significant improvement in the CI over 3D-CRT plans (p <0.001). They also showed statistically significant advantage on the parameters D98%, D95% and D2% of the high dose PTV. Regarding the OARs, mARC plans showed reductions in the mean dose of 3.5 Gy in the bladder and greater than 4 Gy in the femoral heads. Considering the small bowel, the mARC plans resulted in a 2.7 Gy mean reduction in the mean dose and lower irradiated volumes over the entire dose range. Conclusions: Arc therapy plans with the mARC technique for preoperative rectal cancer treatment in a sequential two-phase treatment scheme provide important advantages in the PTVs and OARs. mARC plans show superior protection of the femoral heads, bladder and small bowel, similar to the results found with other more widespread arc therapy techniques. [ABSTRACT FROM AUTHOR]

Estrogen receptor α (ERα) is the major driving transcription factor in the mammary gland development as well as breast cancer initiation and progression. However, the genomic landscape of ERα binding sites in the normal mouse mammary gland has not been completely elucidated. Here, we mapped genome-wide ERα binding events by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) in the mouse mammary gland in response to estradiol. We identified 6237 high confidence ERα binding sites in two biological replicates and showed that many of these were located at distal enhancer regions. Furthermore, we discovered 3686 unique genes in the mouse genome that recruit ER in response to estradiol. Interrogation of ER-DNA binding sites in ER-positive luminal epithelial cells showed that the ERE, PAX2, SF1, and AP1 motifs were highly enriched at distal enhancer regions. In addition, comprehensive transcriptome analysis by RNA-seq revealed that 493 genes are differentially regulated by acute treatment with estradiol in the mouse mammary gland in vivo. Through integration of RNA-seq and ERα ChIP-seq data, we uncovered a novel ERα targetome in mouse mammary epithelial cells. Taken together, our study has identified the genomic landscape of ERα binding events in mouse mammary epithelial cells. Furthermore, our study also highlights the cis-regulatory elements and cofactors that are involved in estrogen signaling and may contribute to ductal elongation in the normal mouse mammary gland. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate methods for the pre-treatment verification of volumetric modulated arc therapy (VMAT) based on the percentage gamma passing rate (%GP) and its correlation and sensitivity with percentage dosimetric errors (%DE). Methods: A total of 25 patients with prostate cancer and 15 with endometrial cancer were analysed. The %GP values of 2D and 3D verifications with different acceptance criteria (1%/1 mm, 2%/2 mm, and 3%/3 mm) were obtained using OmniPro and Compass. The %DE was calculated using a planned dose volume histogram (DVH) created in Monaco’s treatment planning system (TPS), which relates radiation dose to tissue and the patient’s predicted dose volume histogram in Compass. Statistical correlation between %GP and %DE was verified using Pearson’s correlation coefficient. Sensitivity was calculated based on the receiver operating characteristics (ROC) curve. Plans were calculated using Collapsed Cone Convolution and the Monte Carlo algorithm. Results: The t-test results of the planned and estimated DVH showed that the mean values were comparable (P > 0.05). For the 3%/3 mm criterion, the average %GP was acceptable for the prostate and endometrial cancer groups, with average rates of 99.68 ± 0.49% and 99.03 ± 0.59% for 2D and 99.86 ± 0.39% and 99.53 ± 0.44% for 3D, respectively. The number of correlations was poor for all analysed data. The mean Pearson’s R-values for prostate and endometrial cancer were < 0.45 and < 0.43, respectively. The area under the ROC curve for the prostate and endometrial cancer groups, was lower than 0.667. Conclusions: Analysis of the %GP versus %DE values revealed only weak correlations between 2D and 3D verifications. DVH results obtained using the Compass system will be helpful in confirming that the analysed plans respect dosimetric constraints. [ABSTRACT FROM AUTHOR]

Prostate cancer is the second most common cancer diagnosed in men worldwide; however, few patients are affected by clinically significant disease within their lifetime. Unfortunately, the means to discriminate between patients with indolent disease and those who progress to aggressive prostate cancer is currently unavailable, resulting in over-treatment of patients. We therefore aimed to determine biomarkers of prostate cancer that can be used in the clinic to aid the diagnosis and prognosis. Immunohistochemistry analysis was carried out on prostate cancer specimens with a range of Gleason scores. Samples were stained and analysed for intensity of the Seven Transmembrane Epithelial Antigen of the Prostate (STEAP)-1, -2, -3, -4 and the Divalent Metal Transporter 1 (DMT1) proteins to determine suitable biomarkers for classification of patients likely to develop aggressive prostate cancer. Additionally, these proteins were also analysed to determine whether any would be able to predict future relapse using Kaplan Meier analysis. Data generated demonstrated that the protein expression levels of STEAP2 correlated significantly with Gleason score; furthermore, STEAP4 was a significant predictor of relapse. This data indicates that STEAP2 could be potential prognostic candidate for use in combination with the current prostate cancer detection methods and the presence of STEAP4 could be an indicator of possible relapse. [ABSTRACT FROM AUTHOR]

Cytokeratin 19 (KRT19) protein is highly expressed in the epithelium of the gastrointestinal (GI) tract, hepatobiliary tissues, and pancreas of humans and mice. In the present study, we used an improved Cre (iCre) gene to enhance the efficiency of Cre expression in mammalian cells. We established a new transgenic Krt19-iCre bacterial artificial chromosome (BAC) mouse model using the BAC recombineering strategy. Site-specific iCre expression pattern was examined in embryos, adults, and elderly Krt19-iCre mice crossed with Tomato or LacZ reporter mice. Both iCre and reporter protein expressions in adult Krt19-iCre;Tomatoflox/+ (Krt19-iCre Tomato reporter) mice were observed mainly in the epithelial cells of the GI tract, hepatobiliary tissues, and pancreas. However, the expression in the intrahepatic and small pancreatic duct were lower than those in the common bile and large pancreatic duct. In the Krt19-iCre; LacZ reporter embryos, β-galactosidase for the LacZ reporter was expressed in the glandular epithelial cells of the GI tract in 9.5-day embryos, 12-day embryos, and newborn mice. The reporter protein expression in Krt19-iCre-Tomato reporter mice was consistent with the KRT19 expression in human GI tissues. In conclusion, Krt19-iCre BAC transgenic mice can be used to investigate developmental and pathological conditions using the iCre-loxP system. [ABSTRACT FROM AUTHOR]

Objectives: Clinicians should not only know how many patients will benefit from alpha-blocker therapy but should also be able to identify who will benefit. We studied the changes in patient symptoms following alpha-blocker therapy and the predictors of symptom improvement in clinical practice. Design: This was a single-arm, open-label observational cohort study with a 6-week follow-up. Setting: Twenty-two pharmacies in the Netherlands. Participants: Patients were eligible for inclusion if they attended a pharmacy with a new prescription for an alpha-blocker from a general practitioner or urologist. Primary and secondary outcomes: Outcomes were assessed using the International Prostate Symptom Score (IPSS), Overactive Bladder Questionnaire Short Form (OAB-q SF), and Patient Global Impression of Improvement (PGI-I). Demographic, disease-related, and drug-related information were collected to identify predictors of symptom improvement. These predictors were then assessed by logistic and linear regression analyses of both the original data set and an imputed data set that accounted for the missing variables. Results: During the study, 37% of patients with lower urinary tract symptoms perceived clear symptomatic improvement based on the results of the PGI-I. Improvement was more likely in those who still used alpha-blockers at the end of the 6-week study period and in those who used multiple medications. Although symptom scores decreased significantly on the IPSS and OAB-q SF, the only predictor of change was the pretreatment symptom severity. Conclusions: Approximately one-third of our cohort perceived symptom improvement on alpha-blocker therapy. However, we identified no clear predictors of who might benefit from alpha-blocker treatment, indicating that alpha-blockers should still be prescribed on a trial basis. [ABSTRACT FROM AUTHOR]

Metformin, a first-line treatment for type 2 diabetes mellitus (T2DM), has recently been recognized for its pleotropic anti-proliferative, anti-cancer, and anti-aging effects. Contrary to the studies characterizing metformin effects in prostate cancer, little is known about these effects in BPH progression. With the Sample Cohort DB data during 2007 and 2017 from the Health Insurance Review and Assessment Service (HIRA) in South Korea, we investigated the preventative effect of metformin on BPH progression. The study population consisted of 211,648 BPH naïve patients that were diagnosed with BPH in 2009 and a follow-up occurrence of prostatectomy until 2017 that was defined as progression of BPH. These patients were divided into three treatment groups: without T2DM, T2DM without metformin, and T2DM with metformin. The hazard ratio in the T2DM with metformin group was 0.86 for prostatectomy compared to the group without T2DM (CI = 0.77–0.96, P value = 0.007) after adjusting for confounding factors such as age, comorbidity, residential area, level of hospital, and category of BPH medications. The T2DM with high-dose metformin group had a significantly lower risk of prostatectomy with hazard ratio of 0.76 (CI = 0.62–0.92, P value = 0.005) in stratified analysis. Our results suggest that metformin may improve BPH progression based on the reduced risk of prostatectomy, although T2DM effects on BPH were unclear. Future observational studies and prospective trials are needed to confirm the effects of metformin on BPH progression. [ABSTRACT FROM AUTHOR]

In some induced-ovulating species, beta nerve growth factor (β-NGF) has important roles in ovulation, though data for rabbits are still inconclusive. In this study we first synthesized functional recombinant β-NGF from rabbit tissue (rrβ-NGF) to address the following objectives: 1) to compare rabbit β-NGF amino acid sequence with those of other induced- or spontaneous-ovulating species; 2) to assess the effects of rrβ-NGF on rabbit sperm viability and motility, and 3) to examine the in vivo ovulation inducing effect of rrβ-NGF added to the seminal dose in rabbit does. The NGF gene in rabbit prostate tissue was sequenced by Rapid Amplification of cDNA Ends and annotated in GenBank (KX528686). Recombinant rβ-NGF was produced in CHO cells and purified by affinity chromatography. Once confirmed by Western blotting and mass spectrometry (MALDI-TOF) that the amino acid sequence of the recombinant protein corresponded to β-NGF, its functionality was validated in PC12 cells in a successful dose-response study over 8 days. The amino acid sequence of prostate rabbit NGF differed to that of other species mainly in its receptor binding sites. In all the spontaneous ovulating species examined, compared with rabbit, alanine and proline residues, which interact with the high-affinity receptor, were replaced by a serine. In rabbits, asparagine and methionine were substituted by lysine at the low-affinity receptor binding site. In time- and dose-response experiments, the in vitro addition of rrβ-NGF to the ejaculate did not affect sperm viability whereas sperm motility parameters were enhanced by the addition of 1 μg/mL of the neuropeptide. Addition of this same concentration of rrβ-NGF to the seminal dose administered via the intravaginal route in does induced ovulation with a delayed LH peak, leading to a plasma progesterone increase, gestation and delivery. Our findings suggest that rrβ-NGF could be a useful option for biotechnological and reproduction assisted techniques in rabbits but further studies are needed. [ABSTRACT FROM AUTHOR]

Prostate cancer was the most common form and had the second highest death rate of male cancer in the United States in 2015. Current diagnosis techniques, such as prostate-specific antigen tests, transrectal ultrasound scans, and biopsies, are often inconclusive, and in the latter case, invasive. Here, we explore the use of clofazimine hydrochloride nanoparticles (CFZ-HCl NPs), a repurposed formulation from an FDA-approved antimycobacterial agent, as a photoacoustic contrast agent for the evaluation of prostate cancer due to its macrophage-targeting capabilities and high optical absorbance at 495 nm. Using a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model, our results indicate a preferential accumulation of intravenously injected CFZ-HCl NPs in cancerous prostates over normal prostates. Differences in accumulation of CFZ-HCl NPs between cancerous and normal prostates were determined using a two-wavelength unmixing technique via ex vivo photoacoustic imaging. Thus, intravenous injection of CFZ-HCl NPs leads to differences in the interactions of the particles with cancerous vs normal prostates, while allowing for photoacoustic detection and analysis of prostate cancer. These findings could lead to the development of a new noninvasive technique for the detection and monitoring of prostate cancer progression in an animal model that can potentially be translated to human patients. [ABSTRACT FROM AUTHOR]

Nanomedicine is an emerging area in the medical field, particularly in the treatment of cancers. Nanostructured lipid carrier (NLC) was shown to be a good nanoparticulated carrier for the delivery of tamoxifen (TAM). In this study, the tamoxifen-loaded erythropoietin-coated nanostructured lipid carriers (EPO-TAMNLC) were developed to enhance the anti-cancer properties and targetability of TAM, using EPO as the homing ligand for EPO receptors (EpoRs) on breast cancer tissue cells. Tamoxifen-loaded NLC (TAMNLC) was used for comparison. The LA7 cells and LA7 cell-induced rat mammary gland tumor were used as models in the study. Immunocytochemistry staining showed that LA7 cells express estrogen receptors (ERs) and EpoRs. EPO-TAMNLC and TAMNLC significantly (p<0.05) inhibited proliferation of LA7 in dose- and time-dependent manner. EPO-TAMNLC induced apoptosis and G0/G1 cell cycle arrest of LA7 cells. Both drug delivery systems showed anti-mammary gland tumor properties. At an intravenous dose of 5 mg kg-1 body weight, EPO-TAMNLC and TAMNLC were not toxic to rats, suggesting that both are safe therapeutic compounds. In conclusion, EPO-TAMNLC is not only a unique drug delivery system because of the dual drug-loading feature, but also potentially highly specific in the targeting of breast cancer tissues positive for ERs and EpoRs. The incorporation of TAM into NLC with and without EPO coat had significantly (p<0.05) improved specificity and safety of the drug carriers in the treatment of mammary gland tumors. [ABSTRACT FROM AUTHOR]

Radiotherapy is a common treatment option for head and neck cancer patients; however, the surrounding healthy salivary glands are often incidentally irradiated during the process. As a result, patients often experience persistent xerostomia and hyposalivation, which deceases their quality of life. Clinically, there is currently no standard of care available to restore salivary function. Repair of epithelial wounds involves cellular proliferation and establishment of polarity in order to regenerate the tissue. This process is partially mediated by protein kinase C zeta (PKCζ), an apical polarity regulator; however, its role following radiation damage is not completely understood. Using an in vivo radiation model, we show a significant decrease in active PKCζ in irradiated murine parotid glands, which correlates with increased proliferation that is sustained through 30 days post-irradiation. Additionally, salivary glands in PKCζ null mice show increased basal proliferation which radiation treatment did not further potentiate. Radiation damage also activates Jun N-terminal kinase (JNK), a proliferation-inducing mitogen-activated protein kinase normally inhibited by PKCζ. In both a PKCζ null mouse model and in primary salivary gland cell cultures treated with a PKCζ inhibitor, there was increased JNK activity and production of downstream proliferative transcripts. Collectively, these findings provide a potential molecular link by which PKCζ suppression following radiation damage promotes JNK activation and radiation-induced compensatory proliferation in the salivary gland. [ABSTRACT FROM AUTHOR]

Purpose: To develop and validate a classifier system for prediction of prostate cancer (PCa) Gleason score (GS) using radiomics and texture features of T2-weighted imaging (T2w), diffusion weighted imaging (DWI) acquired using high b values, and T2-mapping (T2). Methods: T2w, DWI (12 b values, 0–2000 s/mm2), and T2 data sets of 62 patients with histologically confirmed PCa were acquired at 3T using surface array coils. The DWI data sets were post-processed using monoexponential and kurtosis models, while T2w was standardized to a common scale. Local statistics and 8 different radiomics/texture descriptors were utilized at different configurations to extract a total of 7105 unique per-tumor features. Regularized logistic regression with implicit feature selection and leave pair out cross validation was used to discriminate tumors with 3+3 vs >3+3 GS. Results: In total, 100 PCa lesions were analysed, of those 20 and 80 had GS of 3+3 and >3+3, respectively. The best model performance was obtained by selecting the top 1% features of T2w, ADCm and K with ROC AUC of 0.88 (95% CI of 0.82–0.95). Features from T2 mapping provided little added value. The most useful texture features were based on the gray-level co-occurrence matrix, Gabor transform, and Zernike moments. Conclusion: Texture feature analysis of DWI, post-processed using monoexponential and kurtosis models, and T2w demonstrated good classification performance for GS of PCa. In multisequence setting, the optimal radiomics based texture extraction methods and parameters differed between different image types. [ABSTRACT FROM AUTHOR]

The yak is one of the most important domestic animals in Tibetan life for providing basic resources such as milk, meat and transportation. Although yak milk production is not elevated, yak milk is superior to dairy cow milk in nutrient composition (protein and fat). However, the understanding of the metabolic mechanisms of yak mammary gland tissue during the lactation cycle remains elusive. In this study, GC-MS-based metabolomics was employed to study the metabolic variations in the yak mammary gland during the lactation cycle (pregnancy, lactation and dry period). Twenty-nine metabolites were up or downregulated during the lactation period. Compared to the dry period, during the lactation period the levels of oxalic acid were upregulated, while glycine and uridine were downregulated. Thirty-seven pathways were obtained when the 29 differential metabolites were imported into the KEGG pathway analysis. The most impacted pathways during the lactation cycle were glycine, serine and threonine metabolism; alanine, aspartate and glutamate metabolism; TCA cycle; glyoxylate and dicarboxylate metabolism; and pyrimidine metabolism. Our results provide important insights into the metabolic events involved in yak mammary gland development, lactogenesis and lactation, which can guide further research to improve milk yield and enhance the constituents of yak milk. [ABSTRACT FROM AUTHOR]

In this study, we compared ultrasound (US) features between normal parotid parenchyma (NPP) and incidental diffuse parotid disease (DPD). From January 2008 to December 2017, 180 patients underwent neck US before parotid surgery at our hospital. From these, 82 were excluded because of the lack of histopathological data concerning the parotid parenchyma or inadequate US images. A single radiologist blinded to the clinicoserological data and histopathological results, retrospectively investigated all US features and categorizations for the parotid glands using a picture archiving and communication system. Retrospective histopathological analysis of the parotid parenchyma was performed by a single pathologist. On the basis of the histopathological analyses, the 98 patients were divided into NPP (n = 70) and DPD (n = 28) groups. Among US features, parenchymal echogenicity and echotexture showed statistically significant differences between the two groups (p < 0.0001), whereas the gland size, margin, and vascularity showed no significant differences (p > 0.05). The US-based categorization significantly differentiated between NPP and DPD (p < 0.0001), and receiver operating characteristic curve analysis revealed that US categorization based on ≥2 abnormal US features showed the best diagnostic performance for detecting DPD. Thus, US can aid in differentiating DPD from NPP. [ABSTRACT FROM AUTHOR]

The current study measured the influence of milk of subclinically infected glands by different bacteria species on the cow’s milk. The effects of bacterial infection or inflammation on gland milk yield were related to the bacteria species that caused the infection. The volume of milk of the inflamed gland from the cow’s milk yield was significantly lower (P<0.001) for the glands previously infected by Escherichia coli (PIEc) and those infected with Streptococcus dysgalactiae. Coagulation properties, rennet clotting time (RCT) and curd firmness (CF) also depended on the bacteria causing the infection. RCT values of all the inflamed glands were significantly longer (P<0.001) and CF values were significantly lower than that of the healthy ones. Moreover, in the whole milk, CF was also significantly lower and not proportional to the volume of the milk from the inflamed gland of the cow’s milk. Calculation of the predicted 40% dry matter curd weight (PCW) on the cow level, including the healthy and inflamed glands or the healthy glands alone, showed that for 10 of 13 PIEc cows, the presence of the affected gland’s milk in the whole cow milk resulted in a lower PCW value. Likewise, 7 of 20 cows infected by S. dysgalactiae had negative delta values. Unlike the latter bacteria, PCW from milk of glands infected with CNS increased, although in a lower magnitude than in the healthy glands. No correlation was found between logSCC in the whole cow milk (healthy and inflamed glands) and PCW. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PC) is a multifocal disease. DNA methylation alterations are not restricted to the immediate peritumor environment, but spatially widespread in the adjacent and distant histologically normal prostate tissues. In the current study, we utilized high-throughput methylation arrays to identify epigenetic changes in the urine from men with and without cancer. Design, setting, and participants: DNA urine samples were enriched for methylated fragments using MBD methyl-binding antibodies and applied to high density CytoScanHD arrays. Significant loci were validated using quantitative pyrosequencing and binary logistic regression modeling applied to urine sample analyses in a training (n = 83) and validation approach (n = 84). Methylation alterations in prostate tissues using pyrosequencing at the PLA2G16 locus were examined in 38 histologically normal specimens from men with (TA, n = 26) and without (NTA, n = 12) cancer and correlated to gene expression. Results: Methylation microarrays identified 3,986 loci showing significantly altered methylation in the urine samples from patients with PC compared to those without (TA vs NTA; p<0.01). These loci were then compared against subjects with their prostates removed to exclude non-prostate cell markers yielding 196 significant regions. Multiple CpGs adjacent to PLA2G16 CpG island showed increased methylation in TA compared to NTA (p<0.01) in a large validation study of urine samples. The predictive accuracy of PLA2G16 methylation at CG2 showed the highest predictive value at 0.8 (odds ratio, 1.37; 95% confidence interval, 1.16–1.62; p<0.001). Using a probability cutoff of 0.065, the sensitivity and specificity of the multivariate model was 92% and 35%. When histologically normal prostate tissues/biopsies from patients with PC (TA) were compared to subjects without cancer, significant hypermethylation of PLA2G16 was noted (odds ratio, 1.35; 95% confidence interval, 1.07–1.71; p = 0.01). Conclusion: PLA2G16 methylation defines an extensive field defect in histologically normal prostate tissue associated with PC. PLA2G16 methylation in urine and prostate tissues can detect the presence of PC. [ABSTRACT FROM AUTHOR]

Background: Area-level indices are widely used to assess the impact of socio-environmental characteristics on cancer outcomes. While area-level measures of socioeconomic status (SES) have been previously used in cancer settings, fewer studies have focused on evaluating the impact of area-level health services supply (HSS) characteristics on cancer outcomes. Moreover, there is significant variation in the methods and constructs used to create area-level indices. Methods: In this study, we introduced a psychometrically-induced, reproducible approach to develop area-level HSS and SES indices. We assessed the utility of these indices in detecting the effects of area-level characteristics on prostate, breast, and lung cancer incidence and stage at diagnosis in the US. The information on county-level SES and HSS characteristics were extracted from US Census, County Business Patterns data and Area Health Resource Files. The Surveillance, Epidemiology, and End Results database was used to identify individuals diagnosed with cancer from 2010 to 2012. SES and HSS indices were developed and linked to 3-year age-adjusted cancer incidence rates. SES and HSS indices empirically summarized the level of employment, education, poverty and income, and the availability of health care facilities and health professionals within counties. Results: SES and HSS models demonstrated good fit (TLI = 0.98 and 0.96, respectively) and internal consistency (alpha = 0.85 and 0.95, respectively). Increasing SES and HSS were associated with increasing prostate and breast cancer and decreasing lung cancer incidence rates. The results varied by stage at diagnosis and race. Conclusion: Composite county-level measures of SES and HSS were effective in ranking counties and detecting gradients in cancer incidence and stage at diagnosis. Thus, these measures provide valuable tools for monitoring geographic disparities in cancer outcomes. [ABSTRACT FROM AUTHOR]

Sequencing data have been instrumental in identifying oncogenic drivers in prostatic carcinoma and highlighting biomarkers that define aggressive disease. A review of a series of 30 primary and metastatic prostatic carcinomas clinically sequenced at our cancer genomics laboratory utilizing a targeted gene panel identified recurrent structural variants in the TP53 gene. These structural variants were found in 27% of all sequenced cases and represented 36% of the cases with metastatic disease. TP53 structural rearrangements have been previously reported in a significant subset of osteosarcomas, where they result in loss of p53 protein expression by immunohistochemistry. Similarly, in our prostate cases with TP53 structural rearrangements for which tissue was available for testing, we find loss of p53 protein expression by immunohistochemistry. In the eight TP53-rearranged cases, concurrent PTEN loss was identified in 4 cases, TMPRSS2-ERG fusion in 5 cases, and AR and FOXA1 amplification in 1 case each. Our results from this small case series suggest that TP53 rearrangements with loss of expression represent a frequent alternative mechanism of inactivation of this key tumor suppressor gene with potential utility as a marker of aggressive disease. Recognition of this TP53 rearrangement pathway is essential to accurately identify prostatic carcinomas with loss of TP53 function. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is acute inflammation of the pancreas, mainly caused by gallstones and alcohol, driven by changes in communication between cells. Heparin-binding proteins (HBPs) play a central role in health and diseases. Therefore, we used heparin affinity proteomics to identify extracellular HBPs in pancreas and plasma of normal mice and in a caerulein mouse model of AP. Many new extracellular HBPs (360) were discovered in the pancreas, taking the total number of HBPs known to 786. Extracellular pancreas HBPs form highly interconnected protein-protein interaction networks in both normal pancreas (NP) and AP. Thus, HBPs represent an important set of extracellular proteins with significant regulatory potential in the pancreas. HBPs in NP are associated with biological functions such as molecular transport and cellular movement that underlie pancreatic homeostasis. However, in AP HBPs are associated with additional inflammatory processes such as acute phase response signalling, complement activation and mitochondrial dysfunction, which has a central role in the development of AP. Plasma HBPs in AP included known AP biomarkers such as serum amyloid A, as well as emerging targets such as histone H2A. Other HBPs such as alpha 2-HS glycoprotein (AHSG) and histidine-rich glycoprotein (HRG) need further investigation for potential applications in the management of AP. Pancreas HBPs are extracellular and so easily accessible and are potential drug targets in AP, whereas plasma HBPs represent potential biomarkers for AP. Thus, their identification paves the way to determine which HBPs may have potential applications in the management of AP. [ABSTRACT FROM AUTHOR]

Background: Knowledge about the relationship between PSA, age and ISUP grade group (ISUP) 1 prostate cancer can improve clinical and biological understanding of prostate cancer. We aimed to investigate the associations between PSA and age and the risk of ISUP 1 and ISUP ≥ 2 prostate cancer, respectively. Methods: We included 6 083 men aged 50–69 biopsied with a total of 72 996 individual biopsy cores from the prospective and population based Stockholm3 diagnostic study. We computed the risk of ISUP 1 and ISUP ≥ 2 prostate cancer and their respective associations with PSA and age. Since lower Gleason grades often are masked by higher grades in the overall Gleason score, we compared associations both for overall Gleason score and for Gleason on individual biopsy cores. Results: ISUP 1 prostate cancer was not significantly associated with PSA at diagnosis: odds ratios ranged from 0.82 (95%CI: 0.68–1.00) for PSA 3–4 ng/mL, 0.96 (95%CI: 0.79–1.16) for PSA 4–6 ng/mL, 0.95 (95%CI: 0.75–1.21) for PSA 6–10 ng/mL, and 0.92 (95%CI: 0.58–1.45) for PSA 10–15 ng/mL compared with PSA 2–3 ng/mL. Age was not significantly associated with risk of ISUP 1 cancer. This contrasts to the strong relationship between ISUP ≥ 2 prostate cancer and its respective associations with PSA and age. Conclusions: We find no significant association between the risk of ISUP 1 prostate cancer and PSA and age at diagnosis indicating that PSA contribution from ISUP 1 prostate cancer is closer to that of benign prostate tissue than to that of ISUP ≥ 2 prostate cancer. [ABSTRACT FROM AUTHOR]

We previously reported that overexpression of PODXL, BCL7B, and ARHGEF4 in pancreatic cancer tissue is correlated with pancreatic cancer-related survival. The aim of this study was to investigate the use of PODXL, BCL7B, ARHGEF4, and the integrin family member ITGB1 as useful markers for the prognosis of postoperative pancreatic cancer patients in comparison with tumor size and the tumor node metastasis (TNM) staging system. Immunohistochemistry was performed using an anti-ITGB1 antibody on 102 samples of pancreatic cancer tissue surgically resected at the University of Kochi Medical School Hospital and the Matsuyama Shimin Hospital. Univariate Cox proportional hazards regression analysis showed that TNM stage and overexpression of PODXL, BCL7B, and ITGB1 were correlated with postoperative survival. However, tumor size was not significantly associated with postoperative prognosis of pancreatic cancer compared to these features. Multivariate Cox proportional hazards regression analysis showed that the overexpression of both PODXL and ITGB1 and overexpression of both BCL7B and ITGB1 increased the hazard ratio (6.27, 95% confidence interval [CI] 2.58–15.21; and 3.93, 95% CI 1.74–8.91, respectively) compared to that of TNM stage (IIA and IIB vs. III and IV; 3.05, 95% CI 1.25–7.42). These results imply that the combination of PODXL with ITGB1 and the combination of BCL7B with ITGB1 accurately predicted the postoperative outcomes of pancreatic cancer patients, and they were superior compared to the TNM staging system. The combination of PODXL with ITGB1 would be particularly useful, as it was the most highly correlated with postoperative outcomes. Importantly, the present results are useful to determine which adjuvant therapy should be selected. [ABSTRACT FROM AUTHOR]

In recent years, the role of sympathetic nervous fibers in chronic inflammation has become increasingly evident. At the onset of inflammation, sympathetic activity is increased in the affected tissue. However, sympathetic fibers are largely absent from chronically inflamed tissue. Apparently, there is a very dynamic relationship between sympathetic innervation and the immune system in areas of inflammation, and hence a rapid and easy method for quantification of nerve fiber density of target organs is of great value to answer potential research questions. Currently, nervous fiber densities are either determined by tedious manual counting, which is not suitable for high throughput approaches, or by expensive automated processes relying on specialized software and high-end microscopy equipment. Usually, tyrosine hydroxylase (TH) is used as the marker for sympathetic fibers. In order to overcome the current quantification bottleneck with a cost-efficient alternative, an automated process was established and compared to the classic manual approach of counting TH-positive sympathetic fibers. Since TH is not exclusively expressed on sympathetic fibers, but also in a number of catecholamine-producing cells, a prerequisite for automated determination of fiber densities is to reliably distinct between cells and fibers. Therefore, an additional staining using peripherin exclusively expressed in nervous fibers as a secondary marker was established. Using this novel approach, we studied the spleens from a syndecan-3 knockout (SDC3KO) mouse line, and demonstrated equal results on SNS fiber density for both manual and automated counts (Manual counts: wildtype: 22.57 +/- 11.72 fibers per mm2; ko: 31.95 +/- 18.85 fibers per mm2; p = 0.05; Automated counts: wildtype: 31.6 +/- 18.98 fibers per mm2; ko: 45.49 +/- 19.65 fibers per mm2; p = 0.02). In conclusion, this new and simple method can be used as a high-throughput approach to reliably and quickly estimate SNS nerve fiber density in target tissues. [ABSTRACT FROM AUTHOR]